The present invention relates to a process for preparing piperidylidene dihydro-dibenzo[a,d]cycloheptenes or aza-derivatives thereof and intermediates and individual steps in such process.
Various process for preparing 1, 2, 3 or 4-aza-5-(4-piperidylidene)-10,11-dihydro-dihenzo[a,d]cycloheptene derivatives are disclosed in U.S. Pat. Nos. 3,326,924 and 3,717,647 and Villani et al., Journal of Medicinal Chemistry, 1972, Vol. 15, No. 7, pp. 750-754. For example, one such scheme is as follows: ##STR1## This type scheme has certain disadvantages in that the ring closure steps to the aza-ketone intermediate of formula XVI give relatively poor yields and are labor intensive steps. Also, the reaction of the Grignard reagent with the aza-ketone intermediate of formula XVI can proceed via an undesired 1,6 addition reducing the yield of the desired end product.
U.S. Pat. No. 3,326,924 also discloses other processes proceeding via, for example, 5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]oyridin-11-one as an azaketone intermediate in the preparation of, e.g., azatadine. In one such process, ethyl nicotinate is condensed with phenylacetonitrile to form a keto nitrile. Conversion to the ketone is effected by heating the keto nitrile with a strong mineral acid. Reduction of the so produced 3-pyridyl ketone to a 3-phenethyl pyridine may be carried out by the well-known Wolff-Kishner reaction. The phenethyl pyridine is transformed into its N-oxide by means of a peroxy acid. The N-oxide is then reacted with dimethyl sulfate and then aqueous sodium cyanide to produce a 3-phenethyl-2-pyridylnitrile. The nitrile is cyclized directly to the 5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-one. Althouch this prior art process operates successfully, it would be desirable to use a process which is more economical to provide the aza-ketone intermediate.